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<p>Cell-penetrating peptides (CPPs) are increasingly used for delivering cargo into cells, but the mechanisms of their membrane crossing remain poorly understood, even for shorter cationic hydrophobic peptides. This study explores how cationic hydrophobic peptides with various combinations of cationic (K and R) and hydrophobic (W and I) amino acids interact with lipid bilayers made of 90% neutral lipid 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphocholine (PC) and 10% anionic lipids (either 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphatidylglycerol (PG) or 1,2-dipalmitoyl-<i>sn</i>-glycero-3-phosphoserine (PS)). Specifically, it was found that changing the hydrophobic segment from W to I significantly influences turbidity during the pretransition for the PC/PG mixture. Conversely, in the PC/PS mixture, the interaction with I-peptides causes changes in turbidity during the main phase transition, regardless of whether the cationic segment is R or K. Molecular features analyzed through FTIR spectroscopy revealed significant differences in the vibrations of methylene groups within hydrocarbon chains. In the presence of I-peptides, regardless of whether they are R or K derivatives, a notably higher number of kink conformers were observed compared to W-peptides. Although W-peptides tend to form aggregates due to the insertion of their hydrophobic segments into the lipid bilayer, they appear to maintain the membrane’s integrity and the organization of lipids. In contrast, the branched side chains of the I-segment induce out-of-plane movements in the hydrocarbon chains. As the initial interaction between the peptide and the lipid membrane is crucial for its translocation, these findings provide insights into the molecular events occurring before translocation and emphasize the specifics that make it unique to CPPs.</p> Graphical Abstract <p></p>

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Deciphering the Influence of Side Chains of Short Cationic Hydrophobic Peptides on Macroscopic and Molecular Properties of Mixed Lipid Bilayers

  • 期刊论文

  • 发表日期：

    2026年3月11日

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  • Lea Pašalić,
  • Andreja Jakas,
  • Ana Čikoš,
  • Barbara Pem,
  • Danijela Bakarić

摘要

Cell-penetrating peptides (CPPs) are increasingly used for delivering cargo into cells, but the mechanisms of their membrane crossing remain poorly understood, even for shorter cationic hydrophobic peptides. This study explores how cationic hydrophobic peptides with various combinations of cationic (K and R) and hydrophobic (W and I) amino acids interact with lipid bilayers made of 90% neutral lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (PC) and 10% anionic lipids (either 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (PG) or 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (PS)). Specifically, it was found that changing the hydrophobic segment from W to I significantly influences turbidity during the pretransition for the PC/PG mixture. Conversely, in the PC/PS mixture, the interaction with I-peptides causes changes in turbidity during the main phase transition, regardless of whether the cationic segment is R or K. Molecular features analyzed through FTIR spectroscopy revealed significant differences in the vibrations of methylene groups within hydrocarbon chains. In the presence of I-peptides, regardless of whether they are R or K derivatives, a notably higher number of kink conformers were observed compared to W-peptides. Although W-peptides tend to form aggregates due to the insertion of their hydrophobic segments into the lipid bilayer, they appear to maintain the membrane’s integrity and the organization of lipids. In contrast, the branched side chains of the I-segment induce out-of-plane movements in the hydrocarbon chains. As the initial interaction between the peptide and the lipid membrane is crucial for its translocation, these findings provide insights into the molecular events occurring before translocation and emphasize the specifics that make it unique to CPPs.

Graphical Abstract